Clinical studies have demonstrated that hypoxia accompanies traumatic head injury and is closely associated with poor neurologic outcome. Our long- term objective is to identify the pathologic components of head injury that are augmented by hypoxic insult. As a prerequisite to this objective, we have developed a model of post-traumatic hypoxic brain injury (PTHI) in the rat. Preliminary studies have demonstrated that hypoxic insult after head injury exacerbates vasogenic edema, as measured by brain water content. This proposal focuses on the vasogenic component of PTHI and will examine the mechanism(s) of blood-brain barrier permeability to proteins. Vasogenic edema is characterized in part by breakdown of the blood-brain barrier to plasma proteins. We hypothesize that abnormal protein permeability after traumatic head injury is significantly worsened by hypoxic insult. To test this hypothesis, permeability after traumatic head injury and after PTHI will be analyzed by quantitation of temporal and regional changes in permeability to the plasma proteins horseradish peroxidase, albumin, and IgG. Abnormal permeability may reflect irreversible damage to the endothelial cells. We propose that excessive protein accumulation after PTHI is associated with an increase in transient permeability. To test this hypothesis, semi-quantitative measures will be used to assess permeability to horseradish peroxidase at the ultrastructural level. Recognizing the established role of oxygen-derived free radicals in mediating permeability, we hypothesize that abnormal endothelial permeability after PTHI is in part attributed to oxidative stress and that intervention with superoxide dismutase (SOD) ameliorates this response. Vasogenic edema will be evaluated in injured animals that have been administered liposome-entrapped SOD, an enzyme that catalyzes the dismutation of superoxide anionic radicals. Outcome measures include assessment of permeability to horseradish peroxidase, albumin and IgG. The morphologic basis of free radical mediated permeability is not clearly understood. We hypothesize that brief exposure to oxygen radicals facilitates transendothelial transport of protein in membrane bound vesicles. We will evaluate the influence of oxidative stress on permeability using cultures of cerebral endothelial cells. Protein tracers will be used to define preferential pathways and transmembrane electrical resistance will be evaluated as a measure of tight junction competency. Given the neural toxicity of certain plasma components, we hypothesize that regions of the brain exhibiting marked permeability define neuronal populations that are markedly stressed and/or irreversibly damaged. To test this hypothesis, we will characterize the neuronal and vascular response to PTHI using quantitative histochemistry and immunocytochemical techniques.